In this application for a Mentored Patient-Oriented Research Career Development Award, Del D. Miller will obtain expertise in clinical trials methodology with the intent of studying the biological aspects of antipsychotic response with the goal of improving outcome in persons suffering from schizophrenia. Despite the use of newer atypical agents, many patients with schizophrenia continue to suffer from chronic symptoms and never return to baseline functioning. Dr. Miller will examine plasma concentrations and the presence of mutations of genes that code for neurotransmitter receptors to determine their roles in the clinical response of treatment-refractory persons with schizophrenia receiving clozapine. The candidate proposes a training and research program using the resources of a preventive medicine department devoted to training clinical investigators in the intricacies of treatment trials, a psychiatry department with a long history of research, and a Mental Health Clinical Research Center devoted to the neurobiology of schizophrenia. While Dr. Miller has training in schizophrenia research, he requires additional training in the design of large scale clinical investigations to study the role of biological factors on antipsychotic response. This training will be integrated with a research project seeking: 1) To examine the influence of receptor of polymorphism of the genes that code for neurotransmitter receptors and transporters predicts response to treatment with clozapine 2) To determine whether the combination of clozapine plasma concentrations and presence or absence of genetic polymorphism of neurotransmitter receptors and transporters allows for prediction of response to treatment with clozapine and 3) To develop a model for understanding the relationship between these biological factors and known predictors of clinical outcome. These findings will lead to a therapeutic model for guiding clinicians in choosing treatments for persons with schizophrenia. This award would provide the candidate with the necessary background for further studies of factors influencing antipsychotic response and may yield important algorithms for the pharmacological treatment of schizophrenia. This award will also serve as a mechanism by which the candidate can establish professional collaborative relationships with his mentors and provide him with the background for ongoing research leading to an independent research career.